Kingdom of Bahrain

Arabian Gulf University

College of Medicine and Medical Sciences

Endocrinology

- Short stature:

It is defined as height 2 SD below the mean. It is normal when there is normal growth

velocity (2 inches/year = 5 cm/year) and pathologic when there is decreased growth

velocity.

Determining Mid-Parental Height (MPH):

Males =

Females =

Notice that most children are ±2 SD around their MPH.

How to measure upper-to-lower (U/L) body segment ratio?

Lower segment = from pubic symphysis to t he heel.

Upper segment = total height – lower segment.

Normal ratios:

At birth 1.7

3 years 1.3

< 7 years 1.0

Categorization of short stature:

Endocrinopathies causing short stature:

Growth Hormone (GH) deficiency:

GH is secreted by the anterior pituitary gland.

Clinical features: pathologic short stature (with decreased growth

velocity).

Causes: trauma, CNS irradiation, CNC vascular malformation or brain

tumors.

Investigations: ↓IGF-1 which

must be followed by head MRI to

define the CNS lesion which lead

to this condition.

Management: daily subcutaneous

injections of recombinant GH.

Hypothyroidism:

The most common being

Hashimoto thyroiditis

(autoimmune disease).

Investigations: ↓T4, ↑TSH (due

to loss of negative feedback from

the product) and antithyroid

peroxidase antibodies.

Hypercortisolism:

Prolonged use of external steroids will result in iatrogenic Cushing’s

syndrome (with all of its features).

Turner’s syndrome:

GH treatment has been shown to improve the ultimate height of these

patients.

- Disorders of puberty:

Puberty

Female puberty Male puberty

Onset: 7-13 years.

Thelarche (breast development; 1st sign;

due to estrogen), adrenarche

(pubic/axillary hair development; due to

adrenal androgens) and menarche (onset

of menstruation).

FSH needed for follicular growth; LH

needed for ovulation (usually at day 14).

Onset: 9-14 years.

Testicular enlargement is usually the 1st

sign.

FSH needed for sperm production; LH

needed to stimulate Leydig cells for

testosterone production

Tanner staging:

Precocious puberty كر ب م لوغ ال ب :ال

Is breast development before 7 years of age in females; testicular enlargement

before 9 years of age in males.

Categories:

Premature

thelarche

Breast development in first 2 years of life with no

other secondary sexual characteristics.

Due to transient activation of Hypothalamic-

Pituitary-Gonadal Axis (HPGA).

No treatment needed

Premature

adrenarche

Pubic/axillary hair development without breast

development or testicular enlargement.

It is common in girls after 5 years of age.

No treatment needed.

Central precocious

puberty

It is premature activation of HPGA which is more

common in girls.

Clinical features:

Girls (cause is idiopathic): breast

development, pubic hair and rapid growth

Boys (cause is always organic and head

MRI must be done): testicular enlargement,

pubic hair and rapid growth

Investigations:

↑FSH, LH and sex steroids

GnRH stimulation test: by injecting

synthetic GnRH and watching for ↑LH

(notice that there is flat response in

peripheral precocious puberty).

Peripheral

precocious puberty

Peripheral production of sex steroids independent

of FSH and LH.

Causes: exogenous sex steroids, gonadal tumors or

adrenal tumors.

Clinical features:

Boys: Feminization (gynecomastia) or

premature onset of pubic hair.

Girls: virilization or breast development

Treatment depends on the underlying cause

Delayed puberty:

It refers to no breast development by 13 years in females; no testicular

enlargement by 14 years in males.

Classification:

Hypogonadotropic

hypogonadism

No activation of HPGA

↓FSH, ↓LH and ↓sex steroids

Example: Kallman syndrome (isolated

gonadotropin deficiency associated with anosmia)

Hypergonadotropic

hypogonadism

There is gonadal failure

↑FSH, ↑LH and ↓sex steroids

Examples: Klinefelter syndrome (in boys);

Turner’s syndrome (in girls).

- Ambiguous genitalia:

Sexual differentiation

Male Female

Y chromosome has the SRY gene which will

induce differentiation of gonads to Testes.

Testosterone will be produced by Leydig cells

and stimulate formation of internal ducts.

Testosterone will be converted to DHT by 5α-

reductase stimulating development of external

genitalia.

MIF will be produced by sertoli cells to inhibit

the development of Mullerian duct structures.

Absence of SRY gene will

stimulate gonads to differentiate

to ovaries.

Mullerian duct structures will

develop due to lack of

testosterone and MIF.

External genitalia will not virilize

due to lack of testosterone and

DHT.

- Disorders of adrenal gland:

Adrenal insufficiency

Primary Secondary

Problem is in adrenal gland itself.

Cortisol deficiency: anorexia/weakness,

hyotension and hyponatremia.

Aldosterone deficiency: hyponatremia,

hyperkalemia and acidosis.

Investigation: blunted response with

ACTH stimulation test

Examples: Addison’s disease

(autoimmune destruction of adrenal

cortex by lymphocytic infiltration), CAH

and adrenoleukodystrophy

Problem is at the level of

hypothalamus or pituitary gland

resulting in abnormality in secretion

CRH or ACTH respectively.

Potassium level will be normal because

there is no aldosterone deficiency (it is

not dependent on CRH and ACTH axis).

Examples: prolonged use of steroids for

more than 2 weeks (most common);

pituitary tumors

Congenital Adrenal Hyperplasia (CAH):

It is an AR congenital enzyme deficiency in the adrenal cortex.

21-hydroxylase deficiency (90% of cases):

Classic salt-wasting (cortisol +

aldosterone deficiency)

Girls present with ambiguous

genitalia and electrolyte abnormalities

Simple virilizing (only cortisol

deficiency)

Girls: ambiguous genitalia with no

electrolyte abnormalities

Boys: late-onset, tall stature, penile

enlargement, pubic hair and

advanced bone age

Non-classic (late-onset with only

cortisol deficiency)

Girls: premature adrenarche, rapid

growth, clitoromegaly, acne,

hirsutism and infertility

Boys: premature adrenarche, rapid

growth and premature acne

21 hydroxylase deficiency is diagnosed by: ↑17-hydroxyprogesterone

level.

11β-hydroxylase deficiency: similar to 21-hydroxylase deficiency but patients

are hypertensive and hypokalemic. It is diagnosed by: ↑11-deoxycortisol.

Management: cortisone and fluorocortisol (if there is mineralocorticoid

deficiency).

Cushing’s syndrome:

Clinical features: moon face, nuchal fat pad, central obesity with thin limbs,

purplish striae (mostly on abdomen), hypertension, glucose intolerance and

poor growth.

Causes:

Iatrogenic Most common cause

Cushing’s syndrome Benign or malignant adrenal tumors

Cushing’s disease Excessive ACTH due to pituitary tumors

Investigations:

Gold standard: ↑free cortisol in 24-hour urine collection.

Dexamethasone suppression test: absence of expected cortisol

suppression.

- Type-I DM (insulin-dependent):

Etiology: there is a genetic predisposition (HLA DR3 & DR4) with the trigger of an

environmental factor (such as a viral infection) will result in autoimmune destruction

of β-cells of pancreas by lymphocytic infiltration. Antibodies which play a rule

include:

Islet cell antibodies (ICA): it is present in 85% of patients.

Anti-insulin antibodies.

Anti-GAD antibodies (Glutamic Acid Decarboxylase).

Clinical features: polyuria, polyphagia and polydypsia. Notice that DKA can be the

initial presentation in 25% of patients. Adolescents may present with type-I DM

during their growth spurt due to insulin antagonizing effects of sex steroids.

Diagnosis: FBS > 7 mmol/L; RBG > 11.1 mmol/L and HbA1c > 6.5%

Management:

Insulin:

These are the types of insulin: rapid-acting (e.g. lispro and aspart),

short-acting (e.g. soluble insulin), intermediate-acting (NPH), long-

acting (glargine and detemir).

The most common regimen which is used is: administration of long-

acting insulin at night to provide a 24-hour coverage in addition to

rapid or short-acting insulin with each meal (breakfast, lunch and

dinner).

Monitoring:

Daily blood glucose monitoring using a glucose meter before each

meal and at bed time.

Checking HbA1c which reflects control for the past 3 months.

Watch for hypoglycemia: patients must have parenteral glucagon with

them or simply a source of glucose.

Watch for honeymoon period: transient recovery of residual islet cell

function resulting in endogenous release of insulin.

Watch for Somogyi phenomenon: this occurs when evening doe of

insulin is too high causing hypoglycemia in early morning which

results in release of counter-regulatory hormones that will increase

blood glucose and ketones.

Long-term complications:

Microvascular: nephropathy, neuropathy and retinopathy.

Macrovascular: stroke, MI and hypertension.

- Type-II DM (insulin-independent):

It is known as the adult-type and occurs due to insulin resistance and progressive

decreased insulin production, but nowadays incidence is increased among children

due to obesity!

Clinical features: polyuria, polydypsia, polyphagia, obesity and acanthosis nigricans.

DKA is uncommon.

Management: oral hypoglycemics (such as metformin). Insulin will be used when

there is a failure to control blood sugar with oral hypoglycemics.

- Diabetic Ketoacidosis (DKA):

It is characterized by the triad of: hypeglycemia (> 300 mg/dL), ketonuria and

anion gap metabolic acidosis (pH < 7.3). The acidosis will result in shifting of

potassium outside cells resulting in pseudohyperkalemia.

Pathophysiology:

Due to insulin deficiency there will be diminished glucose at the cellular level

resulting in gluconeogenesis.

High glucose will result in osmotic diuresis with polyuria and eventual

dehydration.

Glucagon release will stimulate the conversion of free FA to ketone bodies

(acetone, acetoacetate and β-hydroxybutyrate).

Clinical features: polyuria, polyphagia, vomiting, dehydration, Kussmaul breathing,

abdominal pain and fruity breath odor.

Management:

Fluid and electrolyte therapy (isotonic saline). Notice that a gradual decline in

osmolality is critical to minimize the risks of cerebral edema which occurs 6-

12 hours into therapy and mortality can reach up to 70%.

Potassium repletion (once urine output is initiated) using the following:

Potassium acetate (50%): managing metabolic acidosis.

Potassium phosphate (50%): shifting ocygen dissociation curve to the

right.

Regular insulin.

- Thyroid disorders:

Hypothyroidism:

General clinical features: proportionate pathologic short stature, goiter (due to

↑TSH), myxedema (puffy dry skin) and amenorrhea in adolescent girls. Other

features include: weight gain, lethargy, constipation and cold-intolerance.

Congenital hypothyroidism:

Causes: thyroid dysgenesis (90% of cases), thyroid dysmorphogenesis,

maternal use of anti-thyroid drugs during pregnancy such as PTU

(which will cause transient hypothyroidism in her baby) or maternal

autoimmune thyroid disease.

Clinical features: defect in neurologic development (thyroid hormones

are important for neurodevelopment in first 2 years of life), large

posterior fontanel, protruding tongue, lethargy, constipation,

myxedema and prolonged jaundice.

Investigations: ↑TSH, ↓T4

Management: L-thyroxine.

Hashimoto thyroiditis:

It is an autoimmune disease in which there will be autoantibodies

directed against thyroid gland causing its destruction and infiltration

with lymphocytes. It occurs more in girls.

Clinical presentation: can be asymptomatic or resulting in goiter and

short stature in addition to other features of hypothyroidism.

Investigations: ↑TSH, ↓T4 and thyroid antiperoxidase antibodies.

Hyperthyroidism:

Clinical features: exophthalmos and lid lag, tachycardia and palptations, warm

and flushed skin, weight loss and diarrhea, tremors and irritability, anlarged

thyroid gland, delayed menarche or gynecomastia in boys.

Grave’s disease:

It is an autoimmune disease which is characterized by the presence of

Thyroid Stimulating Immunoglobulin (TSI) that will bind to receptors

on the surface of thyroid gland mimicking the action of TSH and

producing excessive thyroid hormones. It is considered as the most

common cause of hyperthyroidism in childhood and occurs more in

females.

Investigations: ↓TSH, ↑T3 and T4, (+) TSI

Management:

Anti-thyroid medication PTU or methimazole

Partial thyroidectomy If anti-thyroid medications fail

Radioactive iodine Eventually resulting in permanent

hypothyroidism

- Bone mineral disorders:

Actions of PTH which is secreted by parathyroid gland when calcium levels are

reduced:

Release of calcium and phosphorus from bones (bone resorption).

Reabsorption of calcium from DCT of kidneys.

Excretion of phosphorus by PCT of kidneys.

Stimulating the formation of 1,25 (OH) vitamin D (the active form) by

kidneys thus increasing absorption of calcium from intestine.

Hypocalcemia:

It is defined as ionized calcium < 2.5 mg/dL

Clinical features: seizures or coma (in young patients); tetany (neuromuscular

hyperexcitability) and parasthesias (in older patients).

Causes: hypoparathyroidism (such as in DiGeorge syndrome),

hyperphosphatemia and vitamin D deficiency (causing hypocalcemia with low

phosphorus level).

Management:

Mild asymptomatic hypocalcemia does not require treatment.

Oral calcium: if there are no seizures or there is moderate tetany.

IV calcium gluconate: if patients are more symptomatic.

Rickets:

It is defined as deficient mineralization of growing bone due to vitamin D

deficiency. Vitamin D deficiency occurs due to:

Less exposure to sunlight.

Exclusive breast-feeding (because breast milk is deficient in vitamin

D).

Liver or renal diseases (as metabolism of vitamin D occurs in these

two organs).

It occurs in first 2 years of life and in adolescents when bone growth is most

rapid.

Clinical features: delayed suture closing and widely-opened anterior fontanel,

frontal bossing, craniotabes, rachitis rosary (prominent costochondral

junctions), bowed legs and short stature.

Radiographic findings:

Rickets: distal end of metaphysis of the wrist shows widening, fraying

and cupping.

Healing rickets: line of provisional calcification.

Healed rickets: bone density returns to normal with slight cupping.

Laboratory investigations: ↓vitamin D, normal/↓calcium, ↑PTH, ↓phosphorus

and ↑ALP (due to increase of osteoblastic activity during formation of

excessive osteoids).

Management:

Oral vitamin D (1500-5000 IU/day) for 6-8 weeks.

Shock therapy: 600,000 IU IM injection. The dose is repeated after 2-4

weeks if there is no evidence of healing.

- Diabetes Insipidus (DI):

It is the inability to maximally concentrate urine either due to deficiency in ADH

(central DI) or resistance to ADH (nephrogenic DI). Normally, ADH is synthesize by

hypothalamus and stored in posterior pituitary gland. It is released when there is

increase in serum osmolality to cause reabsoprtion of water from kidneys.

Classification:

Central DI (deficiency of ADH) Nephrogenic DI (resistance to ADH)

Etiology: autoimmune, trauma,

hypothalamic tumors or inherited as

autosomal dominant

Etiology: Inherited as an X-linked

recessive disorder

Clinical features: polyuria, polydipsia, nocturia and enuresis

Investigations: early morning urine sample with specific gravity > 1.018; water

deprivation test (if, at the end of the test, the patient does not respond to administered

ADH, then the patient has nephrogenic DI)

Management: DDAVP -